This proposal responds to the NIA Grand Opportunity call for "Interdisciplinary studies on older persons to identify novel physiologic factors and other mechanisms contributing to impairments in physical function and capabilities, applying innovative imaging technologies and other noninvasive measures, and hi-throughput methods to characterize and analyze multiple phenotypes and potential contributory pathways." Loss of mobility characterized by slowing gait speed, exertional fatigue and exhaustion is a hallmark of age-related functional decline. While decreased mobility is associated with increased muscle fat, decreased muscle mass, and decreased maximal aerobic capacity, current studies using conventional magnetic resonance imaging (MRI), computed tomography (CT), performance tests, and circulating biomarkers have not found a clear biophysiologic basis for age-related slowing and loss of mobility. Studies of mitochondrial function and adenosine triphosphate (ATP) energy production have been, to date, too small to understand the relative roles of the various components of energy metabolism in age-related mobility disability. We hypothesize that decreased skeletal muscle mitochondrial capacity to generate energy plays a pivotal role in age-associated decline in mobility. To test this hypothesis, an interdisciplinary team will lead assessments and analyses of components of the 'energetics system'from muscle oxygen delivery to the energy efficiency of walking. These assessments include phosphorous spectroscopy for in-vivo muscle ATP generation, muscle biopsies with measurements of mitochondrial content and function, blood flow to the legs with exercise, and energy utilization during walking. We will make these measurements in 300 men and women aged 70 to 89 years old who are well characterized for mobility, and exertional fatigue and exhaustion. Participants will be recruited and examined by experienced research centers at the Universities of Pittsburgh, Wake Forest and Arkansas for Medical Sciences, and the study will be coordinated by the San Francisco Coordinating Center. The Study of Energy and Aging (SEA) will have a major impact on science by refocusing research on the physiology of mobility disability, providing a database and specimen bank to test the new paradigm, and establishing the value of novel measurements and developing them for hi-throughput use in this and future multicenter and prospective studies. The SEA database and specimen bank can be used to explore other factors that may contribute to impaired mobility as well as associations between energetics and other aging phenotypes. SEA will impact health care by guiding clinicians to the evaluation of potentially treatable causes of mobility disability and fatigue. Ultimately, this work may identify new modifiable targets for interventions to improve mobility and alleviate fatigue in older adults. PUBLIC HEALTH RELEVANCE: Loss of mobility and fatigue are common consequences of aging, but their causes are unknown. To determine the role of ATP energy generation in this process, experienced geriatric research centers will collect measurements of mitochondrial function from muscle specimens and capacity to generate ATP from muscle spectroscopy, assessments of whole-body capacity to generate ATP energy for walking, and measurements of speed and ability to walk 400 meters including assessment of exertional fatigue and exhaustion. The resulting resource of specimens, images, and data will be available for future studies of the determinants of impaired mobility and fatigue that may identify new modifiable targets for interventions to improve mobility and alleviate fatigue in older adults.